Intermediates for 5-(pyridylalkyl) pyridoindole derivatives

ABSTRACT

5-(PYRIDYLAKYL)PYRIDOINDOLE DERIVATIVES HAVING ANTIALLERGIC ACTIVITY, PREPARED BY THE CONDENSATION OF THE CORRESPONDINGLY SUBSTITUTED 4-PIPERIDONES AND N-AMINO-NARLYAMINOALKYLPYRIDINES, ARE DESCRIBED.

Un d W Paremol Us. or. 260-496 17 Claims ABSTRACT OF THE DISCLOSURE 5-(pyridylalkyl)pyridoindole derivatives having antiallergic activity, prepared by the Condensation of the correspondingly substituted 4-piperid'ones and N-amino-N- arylaminoalkylpyridin es,- are described.

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a division of US. patent application Ser. No. 758,712, filed Sept. 10, 1968, now US. Pat. No. 3,522,262. r a l BRIEF SUMMARY OF THE INVENTION The invention relates to 5-(pyridylalkyl)pyridoindole derivatives, processes and intermediates for the preparation thereof. More particularly, the invention relates to intermediates of the formulas (VII) wherein R R R and R are each independently hydrogen, halogen, lower alkyl, lower alkoxy", lower alkoxycarbonylfor trifluoromethyl, provided that at least one of R R R and R is other than hydrogen; 'R ishydrogen or lower alkyl; and A is tically. acceptable acid addition salts thereof. The compounds of Formulas V, VI, and VII are useful as intermediates in the preparation of the compounds of Formula )I, hereinafter described.

1,3,4,5-tetrahydro-2,8,9-trimethyl-5 a-me v Patented Apr. 4, 1912 In another aspect, the invention relates to the compounds of Formula I, which are useful as antihistaminic and antiallergic agents. f

DETAILED DESCRIPTION OF THEIIN VEN'I'ION The end products of the invention are characterized by the formula wherein R is hydrogen, lower alkyl, benzoyl or benzyl; R R R and R are each independently hydrogen, halogen, lower alkyl, lower alkoxy, lower alkoxycarbonyl, carboxy, hydroxymethyl or trifluoromethyl, provided that at least one of R R R and R is other than hydrogen; R is hydrogen or lower alkyl; and A is R lit 2] .-.--E l I a, l, or taxi wherein R is hydrogen or lower alkyl, and pharmaceutically acceptable acid addition salts thereof.

As used herein, the term lower alkyl is to be understood to mean a straight or branched chain alkyl group of 1 to 6 carbon atoms, such as methyl, ethyl, isopropyl, butyl, pentyl, hexyl, and the like; methyl is preferred. The term halogen is to be understood to mean all of the halogens, i.e., bromine, chlorine, fluorine and iodine; bromine and chlorine are preferred. The term lower alkoxy is to be understood to mean a lower alkyl ether group in which the lower alkyl moiety is as described above, such as methoxy, ethoxy, propoxy, butoxy and the like; methoxy is preferred.

Illustrative of the compounds of Formula I are the following:

8-chloro-1,3,4,S-tetrahydro-Z-methyl-5-(a-methyl-3-pyridylmethyl) -2H-pyrido [4,3-b] indole; 8-ehloro-1,3,4,S-tetrahydro-Z-methyl-S-(a-methyl-Z- pyridylmethyl) -2H-pyrido [4, 3-b] ind ole; 8-chloro-1,3,4,5,-tetrahydro-2-methyl-5-[a-methyl- (6- methyl-2-pyridyl)methyl]-2H-pyrido[4,3-b]indole; S-chloro-l,3,4,S-tetrahydro-Z-methyl-S-[a-methyl-(G- methyl-3 -pyridyl)mehty1] -2H-pyrido [4,3-b] indole; 8-bromo-l,3,4,5-tetrahydro-2-methyl-5-(a-methyl-3-pyridylmethyl) -2H-pyrido [4, 3-b] indole; 8-chloro-1,3,4,S-tetrahydro-Z-methyl-S-(a-methyl-4-pyridylmethyl) -2H-pyrido [4,3-b] indole; 1,3,4,5-tetrahydro-2,S-dimethyl-S-(a-methyl-3-pyridyl- -methyl)-2H-pyrido[4,3-b1indole;- 1,3,4,S-tetrahydro-8-methoXy-2-methyl-5-(a-methyI-S- pyridylmethyl)-2H-pyrido[4,3 b]indo1e; 1, 3 ,4,5-tetr ahydro-2,7,8-trimethyl-5- (a-methyl3-pyridylmethy1)-2H-pyrido[4,3-b]indole; hyl-3-pyridylmethyl)2H-pyrido[4,3-b]indo1e; 1 8- chloro- 1 3,4,5 -tetrahydr'o-2-methyl-5 (3-pyridylmethyl) 2H-pyrido[4,3b]indole; 8-chloro-1,3,4,S-tetrahydrO-Z-methyI-S-(4-pyridyll methyl)-2H-pyrido[4,3-b]indole;.and S-chloro-l,3,4,S-tetrahydro-Z-methyl-S-(2epyridylmethyl)-2H-pyrido[4,3-b]indole.

or R is other than carboxy or'hydroxymethyl, can be pre- Scheme I R, l i--R. 34 EH2 R5 II III V R2 R2 R2 Ra R: t

L0 B4 m an N/ r .1... Hit.

A w I VI 112 11 /Rx N R J?) Pea. i vn vnr} R2 Ra /1 El N R4 wherein R R R R R R and A are as previously described.

In Reaction Scheme I, a substituted aniline of Formula II, which are known compounds or are analogs of known compounds readily obtained by known procedures, is condensed with a pyridine aldehyde or pyridylalkyl ketone of Formula III, which are also known compounds or are analogs of known compounds readily obtained by known procedures, to yield the Schiff base of Formula IV. The condensation is carried out at reflux temperatures, preferably in the presence of an inert organic solvent such as, for example, benzene, toluene and the like. The condensation is suitably carried out at an elevated temperature, preferably at a temperature between about room temperature and the boiling point of the reaction mixture; the preferred temperature range is the reflux temperature of the reaction mixture. Conveniently, an acid catalyst such as paratoluenesulfonic acid and the like may be used to accelerate the reaction.

The Schitf base of Formula IV is converted to the arylaminoalkylpyridine of Formula V utilizing a reducing agent such as, for example, sodium borohydride, or a hydrogenation catalyst, e.g., paladium-on-carbon and the like. Conveniently, an inert organic solvent such as, for example, alkanols. and the like, may be utilized. The reduction issuitably carried out at a temperature in the range of about 25 to 100 C.

The arylaminoalkylpyridine of Formula V is converted to the N-nitrosoamine of Formula VI utilizing a nitro sating agent such as, for example, nitrous acid, which can be conveniently prepared in situ from hydrochloric acid and sodium nitrite. The reaction is suitably carried out in the presence of an inert organic solvent, for example, a lower alkanol such as methanol, ethanol, propanol andthe like, preferably at a low temperature, i.e., at a temperature between about 0 and about 25 C.

The N-nitrosoamine of Formula VI is converted to the N-amino-N-arylaminoalkylpyridine of Formula VII utilizing a reducing agent, preferably a mild reducing agent 75 such as, for example, zinc. 'ri'ed out in the presence efan a ueou-s acid at a rempera The reduction is suitably carture below room temperature, preferably between about 0 and 20 C.

The condensation of the N-amino-N-arylaminoalkylpyridine of-Formula VII with the piperidone of Formula VIII, which are known compounds or are analogs of known compounds readily obtained byknown procedures,-

correspondingly one or more of R2, R R and'R is I methoxycarbonyl, with a reducing agent such as, for ex ample, lithium aluminum hydride and the like.

The compounds of Formula I, wherein one or more of R R R and R is carboxy, can be-prepared by treating the respective compound of Formula I, wherein corre-v spondingly one or more of R R R4 and R is methoxy carbonyl, with a hydrolyzingagent such as, for example,

sodium hydroxide and the like. 1

Preferred end-products of the invention are characterized by the formula V 4 H? Re A Ia wherein R is hydrogen, lower alkyl, benzoyl or benzyl; R and R are each independently hydrogen, halogen, lower alkyl, lower alkoxycarbonyl, carboxy, lower alkoxy, hydroxymethyl or trifluoromethyl, provided that at least one of R or R is other than hydrogen; R is hydrogen or lower alkyl; and A is wherein R is hydrogen or lower alkyl and their pharmaceutically acceptable acid addition salts. Of these, the more preferred are those wherein R is methyl, R and R are chloro, bromo or methyl and R is methyl and the most preferred are those wherein R is methyl, R is chloro, bromo or methyl, R is hydrogen and R is methyl.

The compounds of Formula 1 form acid addition salts and such salts are also within the scope of the invention. The compounds of Formula I form pharmaceutically acceptable acid addition salts with both pharmaceutically acceptable organic and inorganic acids. Suitable organic acids are, for example, maleic acid, fumaric acid,

ascorbic acid, tartaric acid, salicyclic acid, succinic acid, citric acid and the like. Suitable inorganic acids are, for example, the hydrohalic acids, e.g., hydrochloric acid and hydrobromic acid, sulfuric acid, .sulfamic acid, phos phoric acid and the like. The 'acid addition salts are readily obtainable by the usual techniques for the preparation of salts from acids.

The compounds of Formula I of the present invention can be formulated, using conventional inert pharmaceutical adjuvant materials, into dosage forms which are suitable for oral or parenteral administration. Such dosage forms include tablets, suspensions, solutions, etc. Further--- more, the compounds of this invention can be embodied into and administered in the form of suitable hard or soft capsules, The identity of the inert adjuvant materials which are used in formulating the present compounds into oral and parenteral dosage forms will be immediately apparent to persons skilled in the art. These adjuvant materails, either inorganic or organic in nature, include, for example, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols, etc. Moreover, preservatives, stabilizers, wetting agents, emulsifying agents, salts for altering osmotic pressure, buffers, etc. can be incorporated, if desired, into such formulations.

The compounds of Formula I and their pharmaceutically acceptable acid addition salts are distinguishable by their anti-allergic activity, more particularly their antihistaminic activity, and therefore are useful anti-histaminic agents, Particularly pronounced is the anti-allergic activity of 8-chloro-1,3,4,5-tetrahydro-2-methyl-5-(ix-methyl- 3-pyridylmethyl)-2H-pyrido[4,3-b]indole and S-chloro- 1,3,4,5-tetrahydro 2-methyl-5 (2-pyridylmethyl)-2H- pyrido [4,3-b] indole.

The useful anti-histaminic activity of the compounds of Formula I is demonstrated in warm-blooded animals utilizing the standard procedures. For example, five to ten guinea pigs per dose level are orally administered the test compound one hour before intracardial injection of histamine. A 0.55 percent solution of histamine diphosphate is administered at a level of 1 mg./kg. (LD dose. The percent protection from death is used to determine the ED value for the test compound. ED s are calculated by the Miller and Tainter method (Proc. Soc. Exptl, Biol. Med. 57: 261, 1944).

When 8-chloro-1,3,4,5-tetrahydro-2-methyl-5-(2-pyridylmethyl)-2H-pyrido[4,3-b]indole, which has demonstrated an LD of 354 mg./kg. p.o., is utilized as the test substance, an ED of 0.17 is obtained.

When 8-chlor0-1,3,4,5-tetrahydro-2-methy1-5-(ct-methyl-3-pyridylmethyl)-2H-pyrido[4,3-b]indole is utilized as the test substance, an ED of 0.19 is obtained.

The compounds of the Formula I and their pharmaceutically acceptable acid addition salts have effect qualitatively similar to those of chlorpheniramine, known for its therapeutic use and properties. Thus, the compounds of the Formula I demonstrate a pattern of activity associated with anti-allergies of known efficacy and safety.

The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage for the therapeutic effect desired in the species of animal shall be obtained. Obviously several unit dosage forms may be administered at about the same time.

The following nonlimiting example further illustrate the invention. All parts are by weight and all temperatures are in degrees centigrade, unless otherwise men- A mixture of 102 g, of p-chloroaniline, 100 g. of 3- acetylpyridine, 100 mg. of p-toluenesulfonic acid and 600 ml. of benzene was stirred at reflux temperature for 48 hours. The theoretical quantity of water from the reaction was removed by means of a Dean-Stark trap and the reaction mixture was concentrated to a syrup under reduced pressure. The resultant Schiifs base was dissolved in 400 ml. of ethanol. To this solution was added a suspension of 60 g. of sodium borohydride in 400 ml. of ethanol over the course of 2 hours. The reaction mixture was then refluxed for 2 /2 hours and allowed to stand at room temperature overnight.

The solution was then steam distilled to removeany unreacted starting materials and the residue was thoroughly extracted with ether (4x 250 ml.). The ether solution was dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The solid residue was crystallized from a mixture of ethyl acetate and hexane to give 70 g. of 3-[u-methyl-(4-chloroanilino)methyl]pyridine M.P. 121-122".

The base (10.0 g.) was dissolved in ethanol. A slight excess (2.2 moles) of alcoholic hydrogen chloride was added and the solution set in the refrigerator overnight. The precipitate obtained was filtered and recrystallized from ethanol to yield 10.0 g. of 3-[a-methyl-(4-chlor0- anilino)methyl]pyridine dihydrochloride melting at 182- 184.

By the same procedure as is described in detail in this example, the following compounds were prepared:

3 [or-methyl-(p-toluidino)methyl]pyridine, melting at 113, its dihydrochloride salt melting at 187 [from p-toluidine and 3-acetylpyridine];

3-[a-methyl-(p-bromoanilino)methyl] pyridine, melting at 131, its dihydrochloride salt melting at 193l94 [from p-bromoaniline and 3-acetylpyridine];

3 a-methyl- (p-methoxyanilino methyl] pyridine, melting 70-715 [from p-anisidine and 3-acetylpyridine];

3- [oz-methyl (3 ,4-dimethylanilino methyl] pyridine, melting at 91.5-92.5 [rom 3,4dimethylaniline and 3-acetylpyridine];

2-[a-methyl-(4-chloroanilino)methyl]pyridine, melting at 93-945", its dihydrochloride salt melting at 139142 [from Z-acetylpyridine and p-chloroaniline];

2-[a-methyl-(4-chloroanilino)methyl]-6 methylpyridine, melting at -96, its dihydrochloride salt melting at 219-220 [from 2-acetyl-6-methylpyridine and p-chloroaniline];

5-[a-methyl-(4-chloroanilino)methyl]-2 methylpyridine, melting at 114-115 [from Z-methyl-S-acetylpyridine and p-chloroaniline];

3- [or-methyl- (4-chloroanilino)methyl] -4 methylpyridine, melting at 137138 [from 3-acetyl-4-methylpyridine and p-chloroaniline];

4-[a-methyl-(4-chloroanilino)methyl]pyridine, melting at l07-l08, its dihydrochloride salt melting at 196-198" [from 4-acetylpyridine and p-chloroaniline].

EXAMPLE 2 Preparation of 3- [ct-methyl-(4-chloro-N-nitrosoanilino)- methyl] pyridine C 1 C 1 Q m no IIWH 11/ CHCHQ 3- [a-methyl- (4-chloroanilino methyl]pyridine (73 g. was dissolved in 333 ml. of ethanol containing 333 ml. of 1 N hydrochloric acid and cooled to 5 in an ice bath. To this cooled solution was added a solution of 24 g. of sodium nitrite in 166 ml. of water over the course of 1 hour. The temperature was kept between 5-10 during the addition. After the addition was completed, the temperature was allowed to rise to room temperature and the reaction mixture was set aside at room temperature for 18 hours. The oil that separated from the reaction mixture was dissolved in ether and the reaction mix- NaNO l'lCl ture was thoroughly extracted with ether (4X 250 ml.). After drying overnight over anhydrous sodium sulfate the ether solution was concentrated to dryness to yield 5 8' g. of 3- [a-methyl- (4-chloro-N-nitrosoanilino methyl] pyridine as a thick syrup.

By the same procedure as described in detail in this example, the following compounds were prepared:

3- a-methyl- (p-methyl-N-nitrosoanilino methyl] pyridine from 3- a-methyl- (p-toluiaino methyl] pyridine;

3- a-methyl- (p-bromo-N-nitrosoanilino methyl] pyridine from 3- [wmethyl- (p-bromoanilino methyl] pyridine;

3 a-methyl p-methoxy-N-nitrosoanilino methyl] pyridine from 3- [a-methyl- (p-methoxyanilino)- methyl] pyridine;

3- a-methyl- 3,4-dimethyl-N-nitrosoanilino methyl] pyridine from 3- [zx-methyl- (3 ,4-dirnethylanilino methyl] pyridine;

2- a-methyl- (4-chloro-N-nitrosoanilino) methyl] pyridine from 2- [a-methyl- (4-chloroanilino methyl] pyridine;

2- a-methyl- (4-chloro-N-nitrosoanilino) methyl] -6- methylpyridine from 2- a-methyl- (4-chloroanilino methyl] -6-methylpyridine;

5- a-methyl- (4-chloro-N-nitrosoanilino methyl] -2- methylpyridine from 5 [a-methyl- (4-chloro anilino methyl] -2-methylpyridine;

3- wmethyl- (4chloro-N-nitrosoanilino methyl] -4- methylpyridine from 3 [a-methyl- (4- chloroanilino methyl] -4-methylpyridine;

4- [a-methyl- (4-chloro -N-nitrosoanilino) methyl] pyridine from 4- [a-methyl- (4-chloroanilino methyl] pyridine.

EXAMPLE 3 I CHCll:

Over the course of 2 hours 133 g. of zinc dust was added portionwise to a stirred solution of 58 g. of 3-[ozmethyl- (4-chloro-N-nitrosoanilino)methyl] pyridine in 250 ml. glacial acetic acid and 75 ml. of water. During the addition of the zinc the temperature of the reaction mix-- ture was held between 5 by means of an ice-salt bath. After the addition, the mixture was stirred for 1 hour at 5 and then for 1 hour at 35. Water (350 ml.) then added and the reaction mixture was filtered. The filter cake was washed several times with water and the filtrate and the washings were combined. Ice (400 g.) was added and the mixture was made strongly alkaline with 6 N sodium hydroxide. The alkaline mixture was extracted with ester (4X 250 ml.) and the ether extracts were combined and washed with water (4X 100 ml.). When the ether solution had dried overnight over anhydrous sodium sulfate, the desiccant was removed by filtration and the ether was removed by evaporation. 39 g. of 3- [a-methyl-(4-chloro-N-aminoanilino)methyl]pyridine as a thick syrup was obtained.

By the same procedure as described in detail in this example, the following compounds were prepared:

3 a-methyl-(p-methyl-N-aminoanilino methyl] pyridine from 3- a-methyl- (p-methyl-N-nitrosoanilino) methyl] pyridine;

3- a-methyl- (p-bromo-N-aminoanilino methyl] pyridine from 3-[ct-methyl-(p-bromo-N-nitrosoanilino) methyl] pyridine;

3- a-methyl- (p-methoxy-N-aminoanilino) methyl] pyridine from 3-[u-methyl-(p-methoxy-N- nitrosoanilino)methyl]pyridine;

EXAMPLE. 4 p v Preparation of 8-chloro-1,3,4,S-tetrahydrQ-Z-methyl-E(umethyl-3 -pyridylmethyl) -2H-pyrido [4,3-b] indole JIJHCHa A stirred mixture of 14 g. of'3-[a-methyl-(4 -chlor N- aminoanilino)methyl]pyridine, 7.5 g. of l-methylpiperidone-4 and 75 ml. of benzene was heated to reflux. After 24 hours under reflux 0.9 m1; of water wasremoved from the reaction mixture by meansof a Dean-Stark trapand the reaction mixture was concentratedto dryness under reduced pressure. To the stirred residue 56 mLof'IG N alcoholic hydrogen chloride was added in small portions (5 ml.). After the addition was'complete the reaction mixture was refluxed for 0.5 hour, 'allowed'to cool to room temperature and poured onto ice (200 'g.). Sodium hydroxide (6 N) was added until the pH was greater than 10 and the alkaline mixture was extracted. with ether (3x 200 ml.). The ether extractswere combined and dried over anhydrous sodium sulfate overnight. The desiccant was removed by filtration and the ether solution was concentrated to dryness to yield 18 grams of solid 8-chlorol,3,4,5 tetrahydro 2-methyl-5-(dc-methyl-3-pyridylmethyl)-2H-pyrido[4,3-b]indole melting at 107-108. A small portion was recrystallized from hexane and melted at U.v. me 232 mp The base (5.0 g.) was dissolved in ethanol and an excess (2.2 moles) of 6 N alcoholic hydrogen chloridewas' added followed byseveral volumes of ethyl acetate. The solution was set in the refrigerator at 5 for several hours and the precipitate that separated was collected by filtration. Recrystallized from a mixture of ethyl acetate and ethanol, 5.5 g. of 8-ch1oro-l,3,4,S-tetrahydro-Z-methyl-S-(oz-meth- 9 yl-3-pyridylmethyl) -2H-pyrid0 [4,3-b] indole dihydrochloride was obtained, M.P. 223-225 To 1.4 g. of the base dissolved in 10 ml. of warm ethanol was added a solution of 1.0 g. of maleic acid dissolved in 10ml. of a 50 percent-ether mixture. An additional ml. of ether was added carefully to induce crystallization and the mixture was set in the refrigerator for 18 hours to complete the crystallization. The precipitate was filtered and dried to yield 1.5 g. of 8-chloro-l,3,4,5-tetrahydro-2- methyl 5-(a-methyl-3-pyridylmethyl)-2H-pyrido[4,3-b] indole nialeate, M.P. 130131.

By a procedure analogous to that described in detail in this example, and utilizing in place of 3 [a methyl- (4 chloro N amino anilino)methyl] pyridine, a reactant of the formula JIHCH the following compounds were prepared:

10 EXAMPLE 5 Preparation of 3-(4-chloroanilinomethyl) pyridine CHO A mixture of 60 g. of p-chloroaniline, g. of 3- pyridylaldehyde, 100 mg. of p-toluenesulfonic acid and 300 ml. of benzene was stirred and refluxed for 24 hours. By means of a Dean-Stark trap 7 ml. of water was removed from the refluxing mixture during this time and the reaction mixture was then concentrated to dryness under reduced pressure. To the stirred residue dissolved in 250 ml. of ethanol was added g. of sodium borohydride suspended in 400 ml. of ethanol over the course of two hours. Upon completion of the addition, the reaction mixture was refluxed for 3 hours and then steam distilled for 8 hours to remove any unreacted materials.

Reaetant Melting 1 or boiling 2 B1 A Product point/mm.

4-chloro l 8-chloro-1,3,4,5-tetrahydro-2-methyl-5-(a-methyl-Q-pyridyll 1l0111 methyl)-2H-pyrido[4,3-b]indole.

N The maleate salt- 1 154-156 D0 l 8-ehloro-l,3,4,5-tetrahydro-2-methyl-fi-[wmethfl-(G-methyl- 1 2l4-2l6/0.4

2-pyridyl)methyl]-2H-pyrido[4,3-b1indole. F The dihydrochloride salt 1 259261 *CHQ D0 I 8-chl0ro-1,3,4,5-tetrahydro-2-methyl-5-[a-methyl-(ti-methyl- 2 217/0.8

3-pyridyl)methyl]-2H-pyrido[4,3b]indole. LL The maleate salt 2 184l85 4-br0mo 8-brorno-l,3,4,5-tetrahydro-2-methyl-5-(a-methy1-3-pyrldyl 2 230248/0.l5

methyl) -2H-pyrido[4,3-b]indole. L The maleate salt; 1 ll67 I CH3 4-chloro I 8ehlor0-l 3,4,5-tetrahydro-2-methyl-5-(a-methyH-pyridyl- 1 191192 methyl5-2H-py4ido[4,3-b]indole. The dlmaleate hemlhydrte salt 1 l25126 N 4-CH I 1,3,4,5-tetrahydro-2 8-d1methyI-5-(a-methyl-Zi-pyridyl- 2 215225/0.05

methyl)-2H-pyrido[4,3-b]lndole.

L The maleate salt I 17l173 4-CH O Same as above. 1,3,4,5-tetrahydro-8-methoxy-2-methy1-5-(u-methyl-Zi- 225/0.2 pyrldylmethyl)-2H-pyrldo[4,3-b]indole.

The maleate salt 1 -176" 3,4-dimethyl .do 1,3,4,5-tetrahydro-2,7,8-trirnethyl-5-(a-methyl-3pyridyl 2 2052l0/0.03

methyl)-2H-pyrido[4,3-b]lndole.

The maleate salt 1 191-19? D0 410....-. 1,3,4,5-tetrahydro- 2,8,9-trlmethyl-5-(a-methy1-3-pyrldylmethyl)-2H-pyr1do[4,3-b]indole.

The maleate salt l 182183 l Melting point. 2 Boiling point.

The solution was then cooled to room temperature and set in the refrigerator for crystallization. The crystalline 3-(4-chloroanilinomethyl) pyridine (85.2 g.) was collected by filtration, M.P. 95-96". A small portion was recrystallized from ethylacetate and hexane and melted at 98-99".

The base (5.0 g.) was disolved in warm ethanol and an excess of 8 N alcoholic hydrogen chloride was added and the mixture was set in the refrigerator to complete the crystallization. The precipitate obtained was filtered and dried yielding 4.5 g. of 3-(4-chloroanilinornethyl) pyridine dihydrochloride, M.P. 170.

By the same procedure as is described in detail in this example, the following compounds were prepared:

2-(4-chloroanilinomethyl) pyridine, melting at 87, its

hydrochloride salt melting at 170 [from p-chloroaniline and 2-pyridylaldehyde];

4-(4-chloroanilinomethyl) pyridine, melting at 9394, its

dihydrochloride salt melting at 191-192 [from pchloroaniline and 4-pyridylaldehyde];

4-(p-toluidinomethyl) pyridine, melting at 73-74, its dihydrochloride salt melting at l93-194 [from 4-pyridylaldehyde tnd p-toluidine] EXAMPLE 6 By the same procedure as is described in detail in Example 2, the following compounds were prepared:

2-(4-chloro-N-nitrosoanilinomethyl) pyridine, from 2-(4- chloroanilinomethyl) pyridine;

4-(4-chloro-N-nitrosoanilinomethyl)pyridine, from 4-(4- chloroanilinomethyl) pyridine;

4-(p-methyl-N-nitrosoanilinomethyl)pyridine, from 4-(ptoluidinomethyl) pyridine.

EXAMPLE 7 By the same procedure as is described in detail in Example 3, the following compounds were prepared::

2-(4-chloro-N-aminoanilinomethyl)pyridine from 2-(4- chloro-N-nitrosoanilinomethyl)pyridine;

4-(4-chloro-N-aminoanilinomthyl)pyridine from 4-(4- chloro-N-nitrosoanilinomethyl pyridine;

4-(p-methyl-N-aminoanilinomethyl) pyridine from 4- (pmethyl-N-nitrosoanilinomethyl)pyridine.

EXAMPLE 8 EXAMPLE 9' Pharmaceutical formulations incorporating representative products of this invention were prepared as follows:

Tablet formulation Per tablet, mg. 8 chloro 1,3,4,5 tetrahydro 2 methyl (a methyl 3 pyridylmethyl) 2H.- pyrido [4,3-b1indole dihydrochloride 10.0 Lactose 129.0 Corn starch 50.0 Pregelatinized corn starch 8.0 Calcium stearate 3.0

Total wt. 200.0

sy were. theal diyidpa ly "YIPP. 1...

-- Procedure drochloride, lactose, corn starch and pregelat inizedcorn starch were mixed in a suitable mixer. v I

(2) The mix was passed through a Fitzpatrickfcomminuting machine fitted with No. 11A fscreen ajnd with knives forward. f i (3) The mixture was returne d .to the mixer and rn oi s; tened with water to a thick paste. The moist ,,mass was passed through a No. ,12 screem and, the moist granules were dried on paper lined traysgaflloiE- (4) The dried granules were returned'ito the mixer, and the calcium stearate was added and mixed' Well. f: L (5) The granules were compressed at a tabletweight of 200 mg. using standard concave punches having a diameter of Capsule formulation 1 Per capsule, mg.

8 chloro 1,3,4,5 tetrahydro 2 methyl 5- (2 pyridylmethyl) 2H pyrido[4,3-b1indo1e maleate 25.5

Lactose 1159.5 Corn starch 215-29.? .-'P" fie-:92?! 1':- 71, 4.34 Talc 5.0

Suppository. formulation Per 1.3 gm. suppository, gm. 8-chloro 1,3,4,5 tetrahydro 2 -methyl 5- (0c methyl 3 pyridylmethyl) 2H pyrido- [4,3-b]indole dihydrochloride 0.025 Wecobee M (produced by E. F. Drew Company) 522 5th Ave., New York, NY. 1.230 Carnauba wax 0.045

. j- Procedure 1) The Wecobee- M and the carnauba wax were melted in a suitable size glass lined container, mixed well and cooled to 45 C.

(2) 8 chlo o-1.3.45 tetrahydro. -,..-2 methyl -15.- (a methyl 3 pyridylmethyl) 2H pyrido[4,3-b] indole dihydrochloride, which had been reduced to a fine powder with no lumps, was stirred until completely and uniformly dispersed.

(3) The mixture was poured into suppository molds to yield suppositories having an individual weight of 1.3

(4) The suppositories were cooled and removed from paper for packaging.

Parenteral formulation Per ampul 8 chloro 1,3,4,5 tetrahydro 2 methyl (2- pyridylmethyl) 2H pyrido [4,3-b]indole Procedure .(1) 50 grams of 8 chloro 1,3,4,5 tetrahydro 2- methyl 5 (2 pyridylmethyl) 2H pyrido[4,3-b] indole maleate were dissolved in 150 cc. of henzyl alco- 1101; 4,000 cc. of propylene glycol and 1,000 cc. of ethanol were added.

(2) The 12 grams of benzoic acid were dissolved in the above. The 488 grams of sodium benzoate dissolved in 3,000 cc. of water for injection were added. The solution was brought up to final volume of 10,000 cc. with water for injection.

(3) The solution was filtered through an 02 Selas candle, filled into suitable size ampuls, gassed with N and sealed. It 'was then autoclaved at p.s.i. for 30 minutes.

What is claimed is:

1. A compound of the formula wherein R R R and R are each independently hydrogen, halogen, lower alkyl, lower alkoxycarbonyl, lower alkoxy or trifluoromethyl, provided that at least one of R R R and R is other than hydrogen; R is hydrogen or lower alkyl; and A is wherein R is hydrogen or lower alkyl.

2. A compound in accordance with claim 1, wherein R and R are hydrogen.

3. A compound in accordance with claim 2, wherein R is hydrogen.

4. A compound in accordance with claim 3, wherein A is wherein R is hydrogen or lower alkyl.

5. A compound in accordance with claim 3, A is wherein wherein R is hydrogen or lower alkyl.

6. A compound in accordance with claim 3,

wherein A is wherein R is hydrogen or lower alkyl.

7. A compound in accordance with claim 3, R is methyl.

8. A compound in accordance with claim 3, R is hydrogen.

9. A compound in accordance with claim 7, R is halogen or methyl and R is hydrogen.

10. A compound in accordance with claim 8, wherein R is halogen or methyl and R is hydrogen.

11. A compound in accordance with claim 9, methyl- (4-chloro-N-nitro soanilino methyl] pyridine.

12. A compound in accordance with claim 9, methyl-(4-chloro-N-nitrosoanilino)methyl]pyridine.

13. A compound in accordance with claim 10, chloro-N-nitrosoanilinomethyl pyridine.

14. The compound 3 [a methyl (4 chloroanilino) methyl]pyridine.

15. The compound 2 [a methyl (4 chloroanilino) methyH-pyridine.

16. The compound 3-(4-chloroanilinomethyl)pyridine.

17. The compound 2-(4-chloroanilinomethyl)pyridine.

wherein wherein wherein References Cited UNITED STATES PATENTS 2,797,224 6/ 1957 Olfe 260296 R 3,484,449 12/ 1969 Berger et al. 260 -296 T-CY-C 2,786,059 3/1957 Harlein 260296 T-CY-C OTHER REFERENCES Chemical Abstracts, vol. 58: 1428 a (1963) carelli et al. Chem & Pharm Bull, vol. 13: 1135-1137 (1965) Miyano.

Medicinal Chemistry, 2nd edition, Interscience Publishers, (1960) Burger, p. 78.

HENRY R. JILES, Primary Examiner S. D. WINTERS, Assistant Examiner US. Cl. X.R. 

